CCA Risk and Germline Genetics

At the Cholangiocarcinoma Foundation 2024 Annual Conference, Robin Katie Kelley, MD, presented the risk of developing cholangiocarcinoma (CCA) as a byproduct of germline genetics.

In this presentation, she outlined hereditary cancer syndromes (HCSs) that are associated with the risk of biliary tract cancers (BTCs), the prevalence of pathogenic germline aberrations (PGAs) in BTC, and the clinical implications of PGAs in BTC. Notably, the incidence of BTC is rising and is associated with a poor prognosis.^1,2

BTC is heterogeneous and comprises actionable somatic mutations in which tumor next-generation sequencing can help identify candidate germline mutations in a subset of patients with BTC.³

Select HCSs are associated with an increased risk for BTC.

Additionally, some are associated with deoxyribonucleic acid damage response deficiency, such as Lynch syndrome/mismatch repair deficiency, hereditary breast cancer, ovarian cancer, and homologous recombination repair deficiency (HRD). Other HCSs associated with increased BTC risk include those that affect the cell cycle and signaling pathways, such as BAP1 tumor predisposition syndrome.^4,5

Dr Kelley explained that the presence of hereditary cancer mutations plays a crucial role in tumor biology, influencing both prognosis and treatment response, in addition to affecting cancer risk.⁶

In her presentation, Dr Kelley summarized 8 selected BTC cohorts that had undergone germline multigene panel testing from various studies: Memorial Sloan Kettering Cancer Center cohort, a cohort from Hokkaido University Hospital and 4 Japanese hospitals, a Mayo Clinic cohort, a Tianjin Chinese cohort, Peking Union Medical College Hospital cohort, Tempus BTC cohort, Tempus CCA cohort, and the Biobank Japan + Hokkaido cohort. These cohorts were studied to understand the prevalence of PGAs in patients with BTC. The overall prevalence of PGAs in these cohorts was between 4.3% and 16%.^7-14

The prevalence of PGAs in germline HRD was between 2.6% and 5.5%, and in germline BRCA1/2 the prevalence was between 1.2% and 5.3%. PGA prevalence was generally higher in younger patients, patients with a positive family history of cancer, and Asian patients.

There were no consistent differences among intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), or gallbladder cancer (GBC).⁶

A retrospective analysis of patients with iCCA, eCCA, and GBC was conducted within the Tianjin Chinese cohort. It was found that 40 of 382 (10.5%) patients had PGAs or likely PGAs. PGAs were also more common in patients with a family history of cancer (50% vs 28.9%; P=.011).¹⁰

In the Tempus CCA cohort, a retrospective analysis of patients with various solid tumors was done. Results showed that PGAs or likely PGAs were detected in 36 of 840 (4.3%) patients with CCA. Those with PGAs in BRCA1/2 were found in 10 of 840 (1.2%) patients.¹³

In the Biobank Japan + Hokkaido cohort, a retrospective analysis of BTC cases from Biobank Japan and Hokkaido University Hospital was conducted, and it was found that 5.5% of BTC cases and 1.38% of the control group (those without cancer or a family history of cancer) had PGAs.

Additionally, results showed that BRCA1, BRCA2, and MSH6 PGAs were enriched in BTC cases versus the control group (P<.0001 for all). There was also an increased family history of breast cancer in patients with BTC with PGA.¹⁴

PGAs can potentially impact therapeutic outcomes in patients with advanced BTC. For instance, PGAs may be used to predict response to systemic therapies, such as immune checkpoint inhibition in tumors with mismatch repair deficiency.¹⁵

Other response categories could include platinum chemotherapy in HRD tumors and poly ADP-ribose polymerase inhibition in HRD tumors.^16-18

A retrospective case series suggested that BRCA1/2 and other damage response and repair mutations can predict benefit from platinum-based therapy in patients with BTC.¹⁹

In 1 retrospective analysis of patients with CCA harboring germline or somatic BRCA1/2 mutations, there was a median overall survival of 25 months with platinum-based therapy.¹⁹

There are, however, no current guidelines for hereditary cancer testing for patients with BTC. PGA identified in patients with BTC warrants screening for patients and family members for aberrations in BRCA1/2, PALB2, MSI-H/MMR, and BAP1.

The absence of guidelines for PGA testing in BTC is a barrier to providing personalized clinical care for individuals and their affected family members.⁶

References

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3. Valle JW, Kelley RK, Nervi B, et al. Biliary tract cancer. Lancet. 2021;397(10272):428-444.
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6. Kelley RK. Germline genetics and risk of cholangiocarcinoma. 2024 Cholangiocarcinoma Foundation Annual Conference, Presented April 17-19, 2024. Accessed May 21, 2024
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19. Golan T, Raitses-Gurevich M, Kelley RK, et al. Overall survival and clinical characteristics of BRCA-associated cholangiocarcinoma: a multicenter retrospective study. Oncologist. 2017;22(7):804-810.